1. Field of the Invention
The present invention relates to a novel series of 4-substituted-3-substituted-amino-cyclobut-3-ene-1,2-diones having pharmacological activity, to a process for their preparation, to pharmaceutical compositions containing them, and to their use in the treatment of disorders associated with smooth muscle contraction, via potassium channel modulation. Such disorders include, but are not limited to: urinary incontinence, asthma, premature labor, irritable bowel syndrome, congestive heart failure, angina, and cerebral vascular disease.
2. Description of the Prior Art
Modulation of potassium channels remains at the forefront of current approaches for controlling resting cell membrane potential and affecting cell excitability. A wide variety of discrete potassium channels exist and these have been thoroughly classified according to structure, function, pharmacological properties, and gating mechanisms in several recent reviews: Rudy, B. Neuroscience 1988, 25, 729-749; Atwal, K., Medicinal Research Reviews 1992, 12, 569-591; Gopalakrishnan, M. et al., Drug Development Research 1993, 28, 95-127; Primeau, J. et al., Current Pharmaceutical Design 1995, 1, 391-406; Edwards, G. et al., Exp. Opin. Invest. Drugs 1996, 5(11), 1453-1464. Therapeutic potential for potassium channel modulators in cardiovascular disorders, metabolic disorders, central nervous system disorders, bronchial asthma, and irritable bladder is being vastly explored.
A series of N-aryl and N-heteroaryl-1,2-diamino-cyclobutene-3,4-diones disclosed by Butera et al., in U.S. Pat. Nos. 5,354,763; 5,397,790; 5,401,753; 5,403,853; 5,403,854; 5,466,712; 5,506,252 and 5,532,245 and additionally by Antane et al., in U.S. Pat. Nos. 5,464,867 and 5,512,585 have the ability to hyperpolarize smooth muscle tissue via activation of the ATP-dependent potassium channel (KATP). Also disclosed is the potential utility of the N-aryl and N-heteroaryl-1,2-diaminocyclobutene-3,4-diones as useful agents for the treatment of cardiovascular disorders, metabolic disorders, central nervous system disorders, bronchial asthma, and irritable bladder.
A series of 1,2-diamino derivatives of cyclobutene-3,4-diones disclosed by Butera et al., in U.S. Pat. No. 5,763,474 have a pronounced effect on smooth muscle contractility and are useful in the treatment of urinary incontinence, irritable bladder and bowel disease, asthma, hypertension, stroke and similar diseases which are amenable to treatment with potassium channel activating compounds.
Kinney et al., in U.S. Pat. No. 5,240,946 discloses 3,4-diamino-3-cyclobutene-1,2-diones as NMDA antagonists.
Algieri et al., in U.S. Pat. No. 4,390,701 discloses 1-(substituted-amino)-2-(amino or substituted amino)cyclobutene-3,4-diones which are histamine H2 antagonists useful in the treatment of peptic ulcers. Additionally, Nohara, et al., in U.S. Pat. No. 4,673,747 disclose substituted aminoalkylphenoxy derivatives which exert antagonism against histamine H2 receptors.
A series of p-substituted phenyl-cyclobutenediones are reported as substrates and intermediates for monothionation reactions by Muller et al. Synthesis 1997,1,50-52. Related compounds are described by Schmidt et al. Synthesis 1990, 7,579-582 in a paper on Meerwein-arylation of semisquaric acids and semisquaric amides. Unsubstituted phenyl-cyclobutenediones are reported as reaction products between cyclobutenediones and aziridines by Ried et al. Liebigs Ann. Chem. 1975, 1863-1872.
In an effort to generate multiple core structure libraries by combinatorial chemistry, P. A. Tempest et al. J. Am. Chem. Soc. 1997, 119, 7607-7608, using Wang resin, disclose a library of p-hydroxylated phenyl-cyclobutenediones which are prepared and cleaved from the Wang resin to afford hydroxylated phenyl-cyclobutenediones.
N-Substituted-3-amino-4-phenylcyclobutenediones are reported by J. E. Thorpe J. Chem. Soc. (B), 1534-1535(1968) in conjunction with proton nuclear magnetic resonance spectra studies of squaramides.
A series of p-halophenylcyclobutenediones disclosed as intermediates for the preparation of stilbene analogs which are described as having utility as non-linear optical elements with good heat and light resistance are reported in EP-0761643-A2. Additionally, Pu, in U.S. Pat. No. 5,106,997, and Nishikata et al., in U.S. Pat. Nos. 5,616,802, 5,659,085 and 5,811,552 and in JP-A-7-309819 disclose a series of cyclobutenedione derivatives useful for the preparation of nonlinear optical elements.
A series of biphenylcyclobutenediones containing an additional heterocyclic ring as a substituent on the second phenyl ring of the bicyclic moiety and having utility as angiotensin II antagonists are reported in WO9401436-A1.
Additionally, 3-acyl-3-cyclobutene-1,2-diones are reported in several synthetic methodology papers: L. S. Liebeskind et al. J. Org. Chem. 1993,58(13), 3543-3549; L. Sun et al., J. Org. Chem. 1995, 60(25), 8194-8203.
The 4-substituted-3-distributed-amino-cyclobut-3-ene-1,2-diones described herein are useful in the treatment of disorders associated with smooth muscle contraction, via potassium channel modulation.
Accordingly, the present invention discloses compounds represented by Formula (I): 
wherein:
R1, R2, and R3, are, independently hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms (optionally substituted with halogen), cycloalkyl of 3 to 10 carbon atoms, xe2x80x94OR7, amino, alkylamino of 1 to 10 carbon atoms, xe2x80x94SO3H, xe2x80x94SO2NH2, xe2x80x94SONH2, xe2x80x94NHSO2R7, 
xe2x80x94SO2R7, carboxyl, aryl of 6 to 12 carbon atoms or aroyl of 7 to 12 carbon atoms;
A is a moiety selected from the group consisting of a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 and xe2x80x94CHCOR6;
W is selected from the group consisting of carbon and nitrogen and wherein the carbon atom may be optionally substituted with xe2x80x94R1 xe2x80x94R2 and xe2x80x94R3.
R4 is a alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms, wherein the aryl group is optionally substituted with alkyl of 1 to 10 carbon atoms, nitro, halogen, cyano, xe2x80x94OR7, 
trifluoromethyl or trifluoromethoxy;
R5 is hydrogen, alkyl of 1 to 10 carbon atoms, formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, 
xe2x80x94SO2R7, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms;
R6 is alkyl of 1 to 10 carbon or aryl of 6 to 12 carbon atoms;
R7 is alkyl of 1 to 10 carbon atoms (optionally substituted with halogen);
aroyl is benzoyl and naphthoyl which is optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, xe2x80x94CF3, and phenyl;
aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms;
with the following provisos that A is not a bond and W is not a carbon bearing a hydrogen;
a) when R1 and R2 are H; R3 is selected from the group consisting of H, 4-methyl, 4-chloro, 4-nitro and 4-methoxy; and R4and R5 are simultaneously methyl or ethyl;
b) when R1, R2, R3 and R5 are H; and R4 is butyl;
c) when R1, R2 and R5 are H; R3 is 4-halo (chloro, bromo, fluoro, or iodo) and R4 is alkyl of 1 to 4 carbon atoms; and
d) when R1 is selected from the group consisting of H, 2-methyl, 2-ethyl and 2-methoxy; R2 and R5 are H; R3 is 4-dimethylamino and R4 is 2-propyl;
or pharmaceutically acceptable salts thereof.
Preferred groups of compounds of Formula (I) of this invention are those in the subgroups:
a) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, and R5 are as hereinbefore defined;
b) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, and R5 are as hereinbefore defined and W is a carbon bearing a hydrogen;
c) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, and R5 are as hereinbefore defined;
d) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, and R5 are as hereinbefore defined and W is a carbon bearing a hydrogen;
e) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, and R5 are as hereinbefore defined;
f) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, R5 and R6 are as hereinbefore and W is a carbon bearing a hydrogen;
g) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, R5 and R6 are as hereinbefore defined.
More preferred compounds of Formula (I) of this invention are those in the subgroups:
a) compounds having the general formula: 
xe2x80x83wherein:
R1, R2, R3, R4, and R5 are hereinbefore defined and W is a carbon bearing a hydrogen; and
b) compounds having the general formula: 
xe2x80x83wherein:
R1, R2, R4 and R5 are hereinbefore defined, R3 is alkoxy of 1 to 10 carbon atoms and W is a carbon bearing a hydrogen.
Specifically preferred compounds of this invention according to general Formula (I) are the following compounds or pharmaceutically acceptable salts thereof:
3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione;
3-(1,1-Dimethyl-propylamino)-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione;
3-(Isopropyl-methyl-amino)-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione;
3-(4-Methoxy-phenyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione;
3-(4-Methoxy-phenyl)-4-[2-(3-trifluoromethyl-phenyl)-ethylamino]-cyclobut-3-ene-1,2-dione;
(xe2x88x92)-3-(4-Methoxy-phenyl)-1-4-((R)-1-phenyl-ethylamino)-cyclobut-3-ene-1,2-dione;
3-(4-Methoxy-phenyl)-4-(2-phenyl-propylamino)-cyclobut-3-ene-1,2-dione;
3-[2-(4-tert-Butyl-phenyl)-ethylamino]-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione;
4-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]benzonitrile;
3-(4-Trifluoromethyl-phenyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione;
4-(4-Trifluoromethyl-phenyl)-3-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione;
3-(1,1-Dimethyl-propylamino)-4-(pyridin-3-yl)-cyclobut-3-ene-1,2-dione hydrochloride;
3-[2-Oxo-1-(4-trifluoromethyl-phenyl)-propyl]-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione;
3-(4-Bromo-phenyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione;
3-(4-Methoxy-benzyl)-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione one-quarter hydrate;
{2-[1-(4-Methoxy-phenyl)-2-oxo-propyl)]-3,4-dioxo-cyclobut-1-enyl}-(1,2,2-trimethyl-propyl)-carbamic acid tert-butyl ester;
3-(1,1-Dimethyl-2-phenyl-ethylamino)-4-(3-methoxy-phenyl)-cyclobut-3-ene-1,2-dione;
3-[(E)-2-(4-Bromo-phenyl)-vinyl]-4-(1,2,2-trimethyl-propylamino)-cyclobut-3-ene-1,2-dione; and
4-{(E)-2-[3,4-Dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enyl]-vinyl}-benzonitrile.
In particular, this invention also provides a method of treating or inhibiting disorders associated with smooth muscle contraction, via potassium channel modulation in warm-blooded animals in need thereof, which comprises administering to said warm-blooded animals preferably mammals, most preferably humans, an effective amount of a compound of general Formula (II) or a pharmaceutically acceptable salt thereof. 
Wherein:
R1, R2, and R3, are, independently, hydrogen, halogen, nitro, cyano, alkyl of 1 to 10 carbon atoms (optionally substituted with halogen), cycloalkyl of 3 to 10 carbon atoms, xe2x80x94OR7, amino, alkylamino of 1 to 10 carbon atoms, xe2x80x94SO3H, xe2x80x94SO2NH2, xe2x80x94SONH2, xe2x80x94NHSO2R7, 
xe2x80x94SO2R7, carboxyl, aryl of 6 to 12 carbon atoms or aroyl of 7 to 12 carbon atoms;
A is a moiety selected from the group consisting of a bond, xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94 and xe2x80x94CHCOR6;
W is selected from the group consisting of carbon and nitrogen and wherein the carbon atom may be optionally substituted with xe2x80x94R1, xe2x80x94R2 and xe2x80x94R3;
R4 is alkyl of 1 to 10 carbon atoms, cycloalkyl of 3 to 10 carbon atoms, aralkyl of 7 to 20 carbon atoms wherein the aryl group is optionally substituted with alkyl of 1 to 10 carbon atoms, nitro, halogen, cyano, xe2x80x94OR7, 
trifluoromethyl or trifluoromethoxy;
R5 is hydrogen, alkyl of 1 to 10 carbon atoms, formyl, alkanoyl of 2 to 7 carbon atoms, alkenoyl of 3 to 7 carbon atoms, 
xe2x80x94SO2R7, aroyl of 7 to 12 carbon atoms, arylalkenoyl of 9 to 20 carbon atoms, arylsulfonyl of 6 to 12 carbon atoms, arylalkanoyl of 8 to 12 carbon atoms or arylalkylsulfonyl of 7 to 12 carbon atoms;
R6 is alkyl of 1 to 10 carbon atoms, or aryl of 6 to 12 carbon atoms;
R7is alkyl of 1 to 10 carbon atoms (optionally substituted with halogen);
aroyl is benzoyl and naphthoyl which is optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, xe2x80x94CF3, and phenyl;
aryl is naphthyl, phenyl or phenyl optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkylamino of 1 to 10 carbon atoms; or pharmaceutically acceptable salts thereof.
Preferred groups of compounds of Formula (II) of this invention for the method of treating disorders associated with smooth muscle contraction, via potassium channel modulation including pharmaceutically acceptable salts thereof are those in the subgroups:
a) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, and R5 are as hereinbefore defined for Formula (II);
b) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, and R5 are as hereinbefore defined for Formula (II) and W is a carbon bearing a hydrogen;
c) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, and R5 are as hereinbefore defined for Formula (II);
d) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, and R5 are as hereinbefore defined for Formula (II) and W is a carbon bearing a hydrogen;
e) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, and R5 are as hereinbefore defined for Formula (II);
f) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, R5 and R6 are as hereinbefore defined for Formula (II) and W is a carbon bearing a hydrogen;
g) compounds having the general formula: 
xe2x80x83wherein R1, R2, R3, R4, R5 and R6 are as hereinbefore defined for Formula (II).
Preferred compounds of Formula (II) of this invention for the method of treating disorders associated with smooth muscle contraction, via potassium channel modulation including pharmaceutically acceptable salts thereof are those in the subgroups:
a) compounds having the general formula: 
xe2x80x83wherein:
R1, R2, R3, R4, and R5 are hereinbefore defined for Formula (II) and W is a carbon bearing a hydrogen; and
b) compounds having the general formula: 
xe2x80x83wherein:
R1, R2, R4, and R5 are hereinbefore defined for Formula (II), R3 is alkoxy of 1 to 10 carbon atoms and W is a carbon bearing a hydrogen.
For the compounds of Formulae (I) and (II) defined above and referred to herein, unless otherwise noted, the following terms are defined:
Halogen, or halo as used herein means chloro, fluoro, bromo and iodo.
Alkyl as used herein means a branched or straight chain having from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
Cycloalkyl as used herein means a saturated ring having from 3 to 10 carbon atoms and more preferably from 3 to 6 carbon atoms. Exemplary cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Aryl as used here in means a homocyclic aromatic radical, whether or not fused, having 6 to 12 carbon atoms. Preferred adryl groups include phenyl, alpha-naphthyl and beta-naphthyl and the like optionally substituted with one to three substituents each independently selected from the group halogen, carboxy, alkyl of 1 to 10 carbon atoms, nitro, amino, alkoxy of 1 to 10 carbon atoms, and alkyl amino of 1 to 10 carbon atoms.
Aroyl as used herein refers to xe2x80x94C(O)aryl where aryl is as previously defined. Examples include benzoyl and naphthoyl optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, xe2x80x94CF3 and phenyl.
Aralkyl as used herein means an aryl-alkyl group in which the aryl and alkyl group are previously defined. Exemplary aralkyl groups include benzyl and phenethyl.
Alkenyl as used herein means a branched or straight chain having from 2 to 12 carbon atoms and more preferably from 2 to 6 carbon atoms, the chain containing at least one carbon-carbon doubles bond. Alkenyl, may be used synonymously with the term olefin and includes alkylidenes. Exemplary alkenyl groups include ethylene, propylene and isobutylene.
Alkanoyl as used herein refers to xe2x80x94C(O)alkyl where alkyl is as previously defined.
Alkenoyl as used herein refers to xe2x80x94C(O)alkenyl where alkenyl as previously defined.
Alkoxy as used herein means an xe2x80x94O-alkyl group in which the alkyl group is as previously described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
Arylalkanoyl as used herein refers to a carbonyl group or radical directly bonded to an alkyl group of 1 to 10 carbon atoms which is terminally substituted by an aryl group as previously defined, for example phenylacetic acid. The aryl group is optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, CF3, and phenyl and substituted phenyl where the substituents are selected from halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and xe2x80x94CF3.
Arylalkenoyl as used herein refers to a carbonyl group or radical directly bonded to an alkenyl group of 2 to 12 carbon atoms which is terminally substituted by an aryl group as previously defined. The aryl group is optionally substituted with one to three substituents each independently selected from the group halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, xe2x80x94CF3, and phenyl and substituted phenyl where the substituents are selected from halogen, cyano, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms and xe2x80x94CF3.
Arylsulfonyl as used herein refers to the radical xe2x80x94SO2aryl where aryl is as previously defined.
Arylalkylsulfonyl as used herein refers to the radical arylalkylO2Sxe2x80x94 where arylalkyl is as previously defined.
Phenyl as used herein refers to a 6-membered aromatic ring.
Where terms are used in combination, the definition for each individual part of the combination applies unless defined otherwise. For instance, aralkyl refers to an aryl group, and alkyl refers to the alkyl group as defined above.
The range of carbon atoms defines the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituent groups.
Among the specifically preferred compounds of this invention according to general Formula (II) are the specifically preferred compounds of Formula (I) or pharmaceutically acceptable salts thereof for the method of treating disorders associated with smooth muscle contraction via potassium channel modulation.
It is understood by those practicing the art that the definition of compounds of Formulae (I) and (II) when R1, R2, R3, R4, R5, R6 and W contain asymmetric carbons, encompass all possible stereoisomers, mixtures and regioisomers thereof which possess the activity discussed below. Such regioisomers may be obtained pure by standard separation methods known to those skilled in the art. In particular, the definition encompasses any optical isomers and diastereomers as well as the racemic and resolved enantiomerically pure R and S stereoisomers as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof, which possess the activity discussed below. Optical isomers may be obtained in pure form by standard separation techniques or enantiomer specific synthesis. It is understood that this invention encompasses all crystalline forms of compounds of Formulae (I) and (II). The pharmaceutically acceptable salts of the basic compounds of this invention are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, fumaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic and similarly known acceptable acids. Where R1, R2, R3, R4, R5, or R6 contains a carboxyl group, salts of the compounds in this invention may be formed with bases such as alkali metals (Na, K, Li) or alkaline earth metals (Ca or Mg).
The present invention accordingly provides a pharmaceutical composition which comprises a compound of Formula (II) of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
The compounds of the present invention may be prepared according to one or more of the general processes outlined below.
Compounds of Formulae (I) and (II), wherein A is a bond and W, R1, R2, R3, R4 and R5 are hereinbefore defined may be synthesized as shown in Scheme I by the cross-coupling reaction of 3-isopropoxy-4-(tri-n-butylstannyl)-3-cyclobutene-1,2-dione 1 [J. Org. Chem. 1990, 55, 5359-5364] with an appropriate aryl halide 2 or 3-pyridyl-halide (W=N), where X is a halogen and R1, R2 and R3 are hereinbefore defined in a polar solvent such as dimethylformamide (DMF) and the like in the presence of a Pd(O) reagent such as benzylchlorobis(triphenyl-phosphine) palladium (II) and the like in the presence of cuprous iodide to give a substituted-cyclobut-3-ene-1,2-dione intermediate 3 where W and R1, R2 and R3 are hereinbefore defined. 
The resulting substituted-cyclobut-3-ene-1,2-dione intermediate 3 where W and R1, R2 and R3 are hereinbefore defined can then be converted by treatment with the appropriately substituted amine 4 where R4 and R5 are hereinbefore defined in a polar solvent such as ethanol and the like, forming a direct bond, to give vinyligous amide a 5 of Formulae (I) and (II) where R1, R2, R3, R4, R5 and W are hereinbefore defined.
Compounds of Formulae (I) and (II) wherein A=xe2x80x94CHCOR6 and R6 is as described above may be synthesized as shown in Scheme II by reaction of ketone 6 where W, R1, R2, R3 and R6 are hereinbefore defined with diethoxysquaric acid 7 in the presence of a strong base, such as, but not limited to, potassium bis(trimethylsilyl)amide in a solvent such as tetrahydrofuran (THF) or diethyl ether and the like to give ether intermediate 8 where W, R1, R2, R3 and R6 are hereinbefore defined which could then be converted into compounds of Formulae (I) and (II) by treatment with the is appropriately substituted amine 4 in a polar solvent such as ethanol and the like to give compounds of Formulae (I) and (II) where A is a moiety xe2x80x94CHCOR6 and W, R1, R2, R3, R4, R5 and R6 are hereinbefore defined. 
Compounds of Formulae (I) and (II) wherein A is the moiety xe2x80x94CH2xe2x80x94 may be synthesized as shown in Scheme III by a transhalogenation and carbon-carbon bond forming sequence (H. Finkelstein, Ber. 1910, 43, 1528; Stille, J. K., J. Am. Chem. Soc. 1984, 106, 6417) wherein the benzylic iodide coupling partner analogous to 10 is formed in situ in the presence of cuprous iodide and concomitantly reacted with stannane 1. This procedure which is generally applicable to compounds of formula 10, wherein the group Z is either chloride or bromide, avoids the undesirable decomposition endemic to benzylic iodides to give benzyl squarate 11 where W, R1, R2, and R3 are hereinbefore defined. Treatment of benzyl squarate 11 with substituted amine 4 where R4 and R5 are hereinbefore defined gives disubstituted amine squarate 12 of Formulae (I) and (II) where A is xe2x80x94CH2xe2x80x94 and where W, R1, R2, R3, R4, and R5 are hereinbefore defined. 
Compounds of Formulae (I) and (II) wherein A is xe2x80x94CHxe2x95x90CHxe2x80x94 may be synthesized as shown in Scheme IV via jodomethylenation of aldehyde 13 where R1, R2, R3 and W are hereinbefore defined, in the presence of iodoform and chrominum (II) chloride in the absence of light at room temperature(RT) and using the conditions as described by Takai, K., J. Am. Chem. Soc. 1986, 108, 7408, giving vinyl iodide 14 where R1, R2, R3 and W are hereinbefore defined. Using the conditions as described by W. F. Goure et al, J. Am. Chem. Soc., 1984, 106, 6417, vinyl iodide 14 is reacted with stannane 1 in the presence of a Pd(O) reagent such as benzylchlorobis(triphenylphosphine) palladium (II) and the like in the presence of cuprous iodide to give styrenylcyclobutendione ethyl ester 15 where W, R1, R2, and R3 are hereinbefore defined. Further treatment of styrenylcyclobutendione elkyl ester 15 with substituted amine 4 where R4 and R5 are hereinbefore defined in a polar solvent such as ethanol and the like to give disubstituted aminosquarate 16 of Formulae (I) and (II) where A is xe2x80x94CHxe2x95x90CHxe2x80x94 and where W, R1, R2, R3, R4 and R5 are hereinbefore defined. 
As mentioned previously, the compounds of Formula (I) and (II) and their pharmaceutically acceptable salts have been shown in this disclosure to relax smooth muscle. They are therefore useful in the treatment of disorders associated with smooth muscle contraction, disorders involving excessive smooth muscle contraction of the urinary tract (such as incontinence) or of the gastro-intestinal tract (such as irritable bowel syndrome), asthma, and hair loss. Furthermore, the compounds of Formula (I) and (II) are active as potassium channel activators which render them useful for treatment of peripheral vascular disease, congestive heart failure, stroke, anxiety, cerebral anoxia and other neurodegenerative disorders. Moreover, compounds of Formula (I) and (II) mediate their biological effects by activating the large-conductance calcium-sensitive potassium channel (Bkca) or maxiK.
Compounds of the present invention are characterized by their potent smooth muscle relaxing properties in vitro. The compounds of this invention exert their smooth muscle relaxatory activity via activation of potassium channels. In addition, the compounds of the present invention are unique in that they possess intrinsic selectivity for bladder tissue over vascular tissue as demonstrated by bladder/aorta IC50 ratios (Table 1).
The present invention accordingly provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.
The compositions are preferably adapted for oral administration. However, they may also be adapted for other modes of administration, for example, parenteral administration for patients suffering from heart failure.
In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0.1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms contain 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg. Such compositions may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.
The compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent and the like. They are formulated in conventional manner, for example, in a manner similar to that used for known antihypertensive agents, diuretics and xcex2-blocking agents.
The present invention further provides a compound of the invention for use as an active therapeutic substance. Compounds of Formulae (I) and (II) are of particular use in the induction of smooth muscle relaxation.
The present invention further provides a method of treating smooth muscle disorders in mammals, including man, which comprises administering to the afflicted mammal an effective amount of a compound or a pharmaceutical composition of the invention.
The following examples are presented to illustrate rather than limit the methods for production of representative compounds of the invention.